Computer-implemented method for controlling dispensing of a biologically active agent; computer system and software thereof

ABSTRACT

There is provided a computer-implemented method for controlling dispensing of at least one biologically active agent in intermittent doses over discrete predefined time periods, comprising the steps of: (i) initiating the dispensing of the biologically active agent in intermittent doses at a first background dosage rate; and (ii) adjusting to a background dosage rate according to the number of input signals received over each predefined time period from a signalling device.

FIELD OF THE INVENTION

The field of the invention relates to controlling dispensing of abiologically active agent. In particular, the present invention relatesto a computer-implemented method for controlling the dispensing of abiologically active agent; and a computer system programmed to performthe method and software thereof.

BACKGROUND TO THE INVENTION

A conventional mode of labour drug delivery takes the form of constantbackground infusion, where labour drug is administered to a parturientat a constant rate. However, studies have shown that a constantbackground infusion of labour drug may not be ideal, as it is notresponsive to the dynamic and progressive nature of labour pain. Inparticular, there have been conflicting results in literature withregard to the merit of administering a basal infusion as well as itsoptimal infusion rate⁴⁻⁸.

Patient-Controlled Epidural Analgesia (PCEA) is a mode of labourepidural drug delivery which confers greater autonomy and flexibility byenabling the parturient to self-administer boluses of epidural solutionas she deems necessary. Several studies have affirmed the advantages ofPCEA over conventional epidural infusion and it has become establishedas a safe and efficacious mode of labour epidural drug delivery¹⁻³.However, despite extensive research over the last decade, the optimalPCEA program settings have not been elucidated.

SUMMARY OF THE INVENTION

According to the present invention, there is provided acomputer-implemented method for controlling dispensing of at least onebiologically active agent in intermittent doses over discrete predefinedtime periods, comprising the steps of: (i) initiating the dispensing ofthe biologically active agent in intermittent doses at a firstbackground dosage rate; and (ii) adjusting to a background dosage rateaccording to the number of input signals received over each predefinedtime period from a signalling device.

There is also provided a computer-implemented method for controlledadministration of at least one biologically active agent to a subject,comprising the steps of: (i) initiating the dispensing of thebiologically active agent in intermittent doses for administration tothe subject at a first background dosage rate; and (ii) adjusting to abackground dosage rate according to the number of input signals receivedover each predefined time period from a signalling device.

There is further provided a software executable by a computer system tocause the computer system to perform the method according to the presentinvention, and a computer program product comprising said software.

There is also provided a computer system, programmed to perform themethod according to the present invention.

A more complete understanding of the present invention, as well asfurther features and advantages of the present invention, will becomeapparent from the detailed description and figures.

BRIEF DESCRIPTION OF THE FIGURES

Reference numerals indicated in the drawings and referred to in thedetailed description are intended for illustrative purposes only andshould not be construed as limited to the particular structure indicatedin the drawings.

FIG. 1 shows an exemplary delivery system utilizing a computer system 1(e.g. WIFI enabled notebook such as Hewlett Packard Compaq Tablet PC)connected to a signalling device 2 (push-button type switch or patientdemand button”). Program source codes for both the vAMB and PCEA5regimens are loaded into the computer system.

FIG. 2 is a flow chart showing the variable-frequency automatedmandatory boluses (vAMB) algorithm of the present invention.

FIG. 3 is a graph showing the time to the first episode of breakthroughpain for the vAMB and PCEA 5 study groups. The mean survival time beforefirst episode of breakthrough pain was 849.9 min (Standard Deviation;SD=52.2) in Group vAMB and 613.1 min (SD=39.2) in group PCEA5 takinginto account patients who delivered without experiencing breakthroughpain as censored data (p=0.028 by log rank test).

FIG. 4 is a graph showing the mean VAS scores following CSE for the vAMBand PCEA 5 study groups. Mean VAS scores shown up to 10 h post-CSE.Mixed model repeated measurement analysis did not detect any differencein post-block serial pain scores between the two groups. Acomputer-implemented method for controlling dispensing of a biologicallyactive agent according to any aspect of the invention, a computer systemprogrammed to perform the method and software thereof is described inmore detail herein.

The invention may be expressed in terms of a method implemented using acomputer, or alternatively as a computer system programmed to implementthe method, or alternatively as a computer program product (e.g.embodied in a tangible recording, storage medium and/or a computerreadable medium) including program instructions which are operable bythe computer to perform the method.

According to a first aspect, the computer-implemented method forcontrolling dispensing of at least one biologically active agent inintermittent doses over discrete predefined time periods comprises thesteps of:

-   -   (i) initiating the dispensing of the biologically active agent        in intermittent doses at a first background dosage rate    -   (ii) adjusting to a background dosage rate according to the        number of input signals received over each predefined time        period from a signaling device.

The biologically active agent may be for use in administering to asubject. For example, the biologically active agent is for use inepidural administration to a subject.

Accordingly, in a second aspect, there is also provided acomputer-implemented method for controlled administration of at leastone biologically active agent to a subject, comprising the steps of:

-   -   (i) initiating the dispensing of the biologically active agent        in intermittent doses for administration to the subject at a        first background dosage rate; and    -   (ii) adjusting to a background dosage rate according to the        number of input signals received over each predefined time        period from a signalling device.

The input signals may be controlled by a user operating the signalingdevice. In particular, the signaling device may comprise a button whichthe user can press to inflict an input signal. Typically, the inputsignal is generated by a user operating the signalling device. Inparticular, the signalling device is typically connected to the computersystem which receives the input signals over a predefined period, whichin turn controls dispensing of the biological agent, as discussedfurther below. Any suitable signalling device is applicable for themethod of the present invention. For example, the signalling device maybe in the form of a push-button type switch which the user presses togenerate the signal. Alternatively, the signaling device may be in theform of a knob which the user turns to generate the signal. Thesignalling device may be connected to the computer system by anysuitable means. For example, the signalling device may be connected tothe computer system via cables and/or wireless connection. Wirelessconnection includes but is not limited to Wi-Fi and/or Bluetooth.

In particular, the method is suitable for administration of a biologicalagent to a subject. The user generating the input signal may be thesubject who is responsible for self-administration of the biologicalagent according to need. Alternatively, the user generating the inputsignal may be a third party dispensing the biological agent for deliveryto the subject. Such a third party user may generate the input signal asdirected by the subject or based on observing the need of the subject.

The method automatically dispenses an intermittent dose of thebiological agent over each predefined time period. The intermittent dosemay be any suitable dose. For example, the intermittent dose may be 5 mlevery 60 mins. The background dosage rate is calculated based on theautomated intermittent doses; e.g. for an intermittent dose of 5 mlevery 60 min, the background dosage rate is 5 ml/hr.

The first background dosage rate may be any suitable background dosagerate. For example, the first background dosage rate includes but is notlimited to 1 ml/h, 2 ml/h, 3 ml/h, 4 ml/h, 5 ml/h, 6 ml/h, 7 ml/h, 8ml/h, 9 ml/h, 10 ml/h, 11 ml/h, 12 ml/h, 13 ml/h, 14 ml/h, 15 ml/h, 16ml/h, 17 ml/h, 18 ml/h, 19 ml/h, 20 ml/h. In particular, the firstbackground dosage rate may be 5 ml/h.

The predefined time period may be any suitable time period. Thepredefined time period may range between 1 to 60 mins. For example, thepredefined time period may be 3 mins, 5 mins, 10 mins, 15 mins, 20 mins,25 mins, 30 mins, 35 mins, 40 mins, 45 mins, 50 mins, 55 mins or 60mins. In particular, the predefined time period may be 60 mins.

As described, the background dosage rate is adjusted according to thenumber of input signals received over each predefined time period fromthe signaling device. For example, if the frequency of the input signalsincreases, the background dosage rate is increased. For instance, if twoinput signals are received within the first predefined time period of 60mins, the automated intermittent dispensing of the biological agent maybe adjusted to 5 ml doses every 30 mins for the next predefined periodof 60 mins; and the adjusted background dosage rate is 10 ml/h. On theother hand, if the frequency of the input signals decreases, thebackground dosage rate is decreased.

The method may further comprise additionally dispensing a signal-induceddose of the biologically active agent in response to an input signalfrom a signaling device. As an example, if an input signal is received,a first signal-induced dose (e.g. 5 ml) of the biological agent isdispensed. This dose may be dispensed substantially immediately or aftera time period (for example 30 mins) after the signal. If the firstbackground dosage rate is 5 ml/h, the next automated intermittent 5 mldose is dispensed 60 mins after the signal-induced dose (background rate5 ml/h). If a second signal is received over the predefined period of 1h, a second signal-induced dose is dispensed. The next automatedintermittent dose may be adjusted to 5 ml every 30 mins, (backgrounddosage rate of 10 ml/h). If no input signals is received (frequency ofinput signals decreases), the background dosage rate is adjusted down.

The background dosage rate is continuously adjusted over predefined timeperiods for the entire duration of dispensing. The background dosagerate over any subsequent predefined time period may return to the samebackground dosage rate of a previous predefined time period, and even tothe initial background dosage rate.

The input signal includes a signal to dispense a signal-induced dose ofthe biologically active agent and also to adjust the background dosagerate. The overall dosage rate of the biological agent over a predefinedtime period takes into account the background dosage rate (of theintermittent doses) and the signal-induce doses.

The method according to the invention may further comprise applying alockout time period after dispensing each intermittent dose and/orsignal-induced dose wherein no further signal-induced and/orintermittent doses of the biologically active agent are dispensed.According to another example, the method may further comprise applying alockout time period after dispensing each intermittent dose and/orsignal-induced dose wherein no further signal-induced doses of thebiologically active agent are dispensed. This lockout time period is asafety feature. Any suitable lockout time period may be applied. Forexample, the lockout time period includes but is not limited to 5 mins,10 mins, 20 mins, 30 mins or 1 h. For example, the lockout period may be10 mins.

The method may further include the step of generating a signal if thenumber of input signals received from the signaling device exceeds apredefined number. In particular, the signal may be an alarm or ablinking light. The predefined number of input signals may be more thanor equal to 3. More in particular, the predefined number of signals maybe more than or equal to 4.

The method according to the present invention may further comprise thestep of capping the background dosage rate of the intermittent dosesand/or the signal-induced doses at a predefined maximum rate. This isanother safety feature. Any suitable predefined maximum rate may beapplied. The predefined maximum rate includes but is not limited to 5ml/hr, 10 ml/hr, 15 ml/hr, 20 ml/hr, 25 ml/hr or 30 ml/hr. For example,the predefined maximum rate may be 20 ml/hr. Capping the backgrounddosage rate of the intermittent doses and the signal-induced doses isequivalent to capping the overall maximum dosage rate.

The parameters of initial background dosage rate, each adjustedbackground dosage rate, predefined time period, signal-induced dose,lockout time period, predefined number of input signal triggering asignal (e.g. alarm), predefined maximum overall dosage rate may beadapted depending on specific requirements. The biologically activeagent used plays an important role in determining these parameters. Themethod according to any aspect of the invention further includesutilizing at least one dispensing device for dispensing the biologicallyactive agent. Any suitable dispensing device is applicable. For example,the dispensing device comprises a pump and/or a syringe.

The invention also includes a computer system, programmed to perform themethod of the present invention. The computer system may in principle beany general computer, such as a personal computer, a laptop, a notebook,a tablet computer, a workstation or a mainframe supercomputer. Thecomputer system may be enabled for wireless communication and/orconnection. For example, the computer system may be WI-FI and/orBluetooth enabled.

The computer system is operatively connected to the dispensing device.The computer system may be connected to the dispensing device by anysuitable means. For example, the computer system may be connected to thedispensing device via cables and/or wireless connection. Wirelessconnection includes but is not limited to Wi-Fi and/or Bluetooth.

Accordingly, there is provided a dispensing system comprising a computersystem operatively connected to at least one dispensing device, whereinthe dispensing system is configured to perform the method of the presentinvention.

There is also provided a software executable by a computer system tocause the computer system to perform the method according to any aspectof the present invention. The software comprises an algorithm, thevariable-frequency automated mandatory boluses (vAMB) algorithm. Anexample of the vAMB algorithm is shown in FIG. 2.

Further provided a computer program product comprising a softwareexecutable by a computer system to cause the computer system to performthe method according to any aspect of the present invention. Thecomputer program product according to an aspect of the invention maycomprise a tangible computer program product. In particular, thetangible computer product may comprise a tangible recording, storageand/or computer-readable media. The Invention is suitable for thedelivery and/or administration of any suitable biological agent to asubject. For example, the biological agent may comprise an analgesic oran anesthetic. Any route of administration is applicable. For example,the administration comprises epidural administration. In particular, theinvention is suitable for labour drug delivery to parturient. Theinvention is particularly suitable for combined spinal-epiduralanalgesia. As additional examples, the biologically active agentincludes but is not limited to ropivacaine, fentanyl, lidocaine, and thelike.

Having now generally described the invention, the same will be morereadily understood through reference to the following examples which areprovided by way of illustration, and are not intended to be limiting ofthe present invention.

EXAMPLES

This study compares administering variable-frequency automated bolusesat a rate proportional to the patient's needs, in place of a fixedcontinuous basal infusion in a PCEA regimen. A complex software programwhich enables an ordinary syringe pump to function as a PCEA pump withthe ability to deliver variable-frequency automated mandatory boluses(vAMB) in addition to patient-driven PCEA boluses (FIG. 1) was designed.This program was compared with a conventional PCEA with a basal infusionof 5 mL/h which is the standard regimen used at our institution. Theprimary outcome of interest was the incidence of breakthrough painrequiring anesthesiologist supplementation.

This study was conducted with the approval of the hospital ethicscommittee and written informed consent was obtained from everyparturient who participated in the study. We recruited 102 healthy(American Society of Anesthesiology Classification ASA I) nulliparousparturients with term gestations (defined as >36 weeks of gestation) andsingleton fetus, who were in early labour (cervical dilation <5 cm) andwho had requested labour epidural analgesia.

Parturients with multiple pregnancies, non-cephalic presentations, andobstetric complications (e.g. pre-eclampsia and premature rupture ofamniotic membranes) were excluded from our study. Parturients who hadcontraindications to neuraxial blockade or who had received parenteralopioids within the last 2 hours were also excluded.

After establishing intravenous access, a non-invasive blood pressuremonitor cuff (Dinamap, Critikon, Fla.) was applied over the parturient'sright brachial artery. Baseline systolic blood pressure and heart ratewere measured in the supine position with left uterine displacement.Each parturient was pre-loaded with 500 ml of IV Ringer's Lactatesolution. A baseline visual analog pain score (VAS) based on a 0-10 cmscale was obtained from the parturient during a uterine contraction, andonly those who had a VAS >3 cm were recruited into the study. Pre-blockdata such as the cervical dilatation prior to neuraxial blockade, use ofcervical prostaglandin E2 for induction of labour, artificial rupture ofmembranes and administration of IV oxytocin for labour augmentation wererecorded.

Combined spinal-epidural (CSE) analgesia was explained to eachparturient and informed consent obtained as per institution protocol.All neuraxial blocks were performed by a single operator at the L3-4interspace using the needle-through-needle technique with the patientsitting up. The epidural space was located with an 18-gauge Tuohy needle(Espocan, B. Braun, Melsungen, Germany) using loss of resistance to <2ml of saline. A 27-gauge pencil point needle was then used to puncturethe dura mater and free flow of cerebrospinal fluid (CSF) was confirmedbefore a standardized intrathecal dose of ropivacaine 2 mg (Naropin,Astra Zeneca, Södertälje, Sweden) and fentanyl 15 μg (David BullLaboratories, Melbourne, Australia) was injected over 15 seconds withthe needle orifice facing cephalad. A multiorifice catheter (Perifix®,B. Braun, Melsungen, Germany) was inserted into the epidural space up toa length of 4 cm in-situ. A test dose of 3 ml of 1.5% lidocaine(Xylocalne, Astra Zeneca, Södertälje, Sweden) was administered throughthe catheter following negative aspiration for blood and CSF. Thepatient was then placed supine with left lateral uterine displacementand post-block profile was recorded. If a profound motor block (definedas an inability to flex either knee) or significant hypotension (areduction of systolic blood pressure >30%) developed within the next 15mins, the patient would be withdrawn from the study due to suspectedintrathecal catheter misplacement. Patients with recognised accidentaldural punctures, intravascular catheter placement and those in whomthere was a failed spinal (defined as failure to obtain cerebrospinalfluid backflow following two dural punctures with the spinal needle),were also excluded from the study and managed according to departmentalprotocols.

The parturients were randomly allocated into two groups using sealedopaque envelopes and computer-generated random number tables by anindependent assistant, who then programmed the epidural drug deliverysystem according to group assignment. The parturients were subsequentlymonitored by a second anesthesiologist who was not involved inperforming the block. Neither the parturients nor the anesthesiologistswho recorded the post-block data were aware of their group assignment.

The parturients were randomized to receive 0.1% ropivacaine+fentanyl 2μg/ml via one of the following regimens for maintenance of labourepidural analgesia:

1. PCEA with basal continuous infusion (Group PCEA5): PCEA with basalinfusion 5 ml/h initiated immediately following intrathecal drugadministration (noted as Time 0). PCEA self-bolus was set at 5 ml,lockout interval at 10 min and maximal dose at 20 ml/h (inclusive ofbackground infusion).2. PCEA with variable automated mandatory boluses (Group vAMB): PCEAvAMB algorithm as illustrated in FIG. 2, initiated immediately aftercompletion of CSE. This pump was designed to administer intermittentmachine boluses of 5 ml in addition to the patient-controlled boluses.The frequency of such automated machine boluses (AMB) would be dependenton the history of the patient's analgesic requirement over the pasthour. The first AMB dose was programmed to be delivered 60 min from Time0 and every hour thereafter if no PCEA patient-bolus were made(background rate 5 ml/h). At the first activation of a PCEApatient-bolus, the timer would be reset with the subsequent AMBdelivered 30 min following the PCEA patient-bolus, and every hourthereafter if no further PCEA patient-bolus were made (background rate 5ml/h). If there was a second PCEA patient-bolus in that same hour, thetime interval between two AMB would be shortened to 30 min (backgroundrate 10 ml/h). If there was a third PCEA patient-bolus within that hour,the AMB would be delivered at 20 min intervals (background rate 15ml/h). A fourth PCEA patient-bolus within the same hour would furthershorten the time interval between two AMBs to 15 min (background rate 20ml/h). On the other hand, if there were no patient-bolus for, the wholeof 60 min, the frequency of AMB boluses would step down in the reversefashion. The lockout period for both PCEA and AMB boluses was 10 min. Ifa PCEA demand was made within 10 min of an AMB dose, no patient-boluswould be given and this would be recorded as an unsuccessful PCEAattempt. PCEA bolus was set at 5 ml and the maximal hourly limit was setat 20 ml/h (inclusive of automated boluses).

In one example, the AMB would be delivered during the lockout period ofthe patient's bolus because AMB is considered as the ‘background rate’;however, if the AMB is scheduled to substantially coincide with the timeof the patient's bolus, then no further AMB will be given at that pointin time.

Our institution collaborated with computer engineers to create asoftware program that allows an ordinary syringe driver to function as aPCEA, with the ability to deliver background mandatory boluses inaddition to patient-demand boluses. An epidural drug delivery systemutilizing a Hewlett Packard Compaq 2710p Tablet PC operating onMicrosoft Windows XP Tablet PC Edition 2005 (Microsoft, USA) connectedto a modified B. Braun Perfusor® Compact S infusion pump (B. Braun,Melsungen, Germany) was developed (FIG. 1). Program source codes forboth the vAMB and PCEA5 regimens were loaded into the Tablet PC. Thetwo-way communication between the pump and the HP Tablet PC wasaccomplished by connecting the pump serial ports to the USB port on theTablet PC. The 5 ml automated machine-boluses as well as PCEApatient-boluses were time-cycled, based on an infusion rate of 100 ml/hand required three minutes to complete. Both programs underwent rigorousin-vitro testing at our institution's Biomedical Engineering Unit and byall investigators independently before being applied to patients in aclinical setting.

Once the parturient reported a VAS <3 cm 15 min after CSE, she would begiven a hand-held device and instructed to self-administer a PCEA bolusby pressing the button on the device once she experienced a recurrenceof pain. She would be counselled to activate the PCEA bolus even if thepain was only mild, before it increased in severity. She would also beinformed about the purpose of a lockout period and maximal hourly doselimit. Parturients who did not obtain satisfactory pain relief (definedas VAS <3 cm) 15 min after CSE were deemed to have an ineffectivespinal. The epidural catheter would then be used to administer rescueanalgesia and the patient removed from the study.

The following parameters were monitored by an independentanesthesiologist after the block:

1. Systolic blood pressure and heart rate every 5 min for the first 30min and subsequently at 2 h intervals until delivery2. Continuous fetal heart rate monitoring3. VAS 15 and 30 min from Time 0 and subsequently at 2 h intervals untildelivery4. Sensory block height (loss of cold sensation to ice tested at themid-clavicular line bilaterally) 15 and 30 min from Time 0 andsubsequently at 2 h intervals until delivery5. Degree of lower limb motor blockade 15 and 30 min from Time 0 andsubsequently at 2 h intervals until delivery, based on the modifiedBromage scale (0=no motor block, 1=unable to flex either hip but able tomove knee and ankle joints, 2=unable to flex hip and knee joint ofeither limb but able to move ankle joints, 3=unable to move hip, knee orankle joint of either limb)6. Post-block side effects such as shivering, nausea, vomiting,pruritus, maternal pyrexia, significant maternal hypotension (defined assystolic BP <90 mmHg or >25% decrease from baseline) and fetalbradycardia requiring review by an independent obstetrician. Treatmentfor maternal hypotension and fetal bradycardia was administered as perinstitution protocol i.e. IV ephedrine in 5 mg aliquots if maternalhypotension was present, and IV terbutaline 0.25 mg if uterinehyperstimulation was diagnosed.7. Time of first patient-activated PCEA demand-bolus.

The parturients were instructed to inform the attending anesthesiologistif they experienced inadequate pain relief (VAS 3 cm or more) whilst onPCEA therapy. Additional pain relief would then be administered by theanesthesiologist via the indwelling epidural catheter and this wouldconstitute an episode of breakthrough pain. According to departmentalguidelines, the attending anesthesiologist would administer epidural0.2% ropivacaine in 5 ml aliquots every 10 min (up to a maximum of 20ml) until VAS <3 cm. Fentanyl 50 mcg was added if VAS remained ≧3 cmafter 10 ml of epidural 0.2% ropivacaine had been given. The pumps werepaused for the duration of time taken to administer each clinicianbolus, and resumed immediately after. Such clinician-administered manualboluses did not affect the PCEA pump settings in any way. The episode ofbreakthrough pain was concluded once the parturient reported a VAS <3cm. The following data was recorded at each episode of breakthroughpain: time of occurrence, pain scores, cervical dilation, use ofoxytocin and total dose of epidural medication needed to abolish thepain. If the epidural top-up failed to achieve adequate analgesia(defined as VAS <3 cm), the catheter was deemed ineffective and theparturient would also be removed from the study.

Obstetrical and neonatal outcomes such as mode of delivery (vaginal,instrumental or cesarean delivery), indication for instrumental orcesarean delivery, duration of second stage of labour and neonatal Apgarscores at 1 and 5 min were noted. The parturient would be interviewedwithin 24 h of delivery by a separate anesthesiologist not involved inthe study for an overall assessment of her satisfaction with labouranalgesia (graded on a verbal scale from 0 to 100, with 0 being verydissatisfied and 100 being extremely satisfied).

A sample size of 49 patients in each group was required to detect a 20%reduction in the incidence of breakthrough pain requiring physiciantop-up for patients in the vAMB arm compared with those in the PCEA5 arm(α=0.05, β=0.2). A reduction in the incidence of breakthrough pain froma baseline of 25% at our institution to 5% was deemed clinicallysignificant, as this could potentially improve patient satisfaction andreduce clinician workload in a busy obstetric unit like ours. All dataand statistical analyses were managed with SPSS version 15 (SPSS Inc.,Chicago, Ill., USA). The Student's t-test was used for the analysis ofcontinuous data that was normally distributed and the Mann Whitney testemployed for nonparametric data. For categorical data and proportions,the χ2 test with Yates correction (where appropriate) was applied.Kaplan Meier survival analysis was used to compare the duration ofeffective analgesia after CSE prior to the first episode of breakthroughpain requiring epidural top-up by an anaesthesiologist (if any). If theparturient delivered without experiencing breakthrough pain, theinterval from Time 0 to delivery was computed as the censored data inthe eventual Kaplan Maier analysis. The mean survival times to the firstepisode of breakthrough pain were analyzed using the log rank test.

For analysis of serial measurements such as pain scores and sensorylevels, the Mixed Model repeated measurement analysis technique wasemployed to adjust for missing data at time intervals after theparturients had delivered and the epidural infusion had been stopped.

All 102 recruited parturients completed the study. Baseline demographicand pre-block obstetric data were similar for parturients in both groups(Table 1). None of the patients had a failed spinal or an ineffectiveepidural catheter. There were no patients who had inadvertentintravascular catheter misplacement or accidental dural puncture.

TABLE 1 Patient's baseline demographic and preblock obstetric data VAMBPCEA5 P = (N = 51) (N = 51) VALUE BMI (kg/m²) 27.3 (3.9) 28.2 (4.9) 0.32Cervical dilatation preblock 3.2 (0.7) 3.2 (0.9) 0.86 (cm) Maternalsystolic BP 113.8 (10.6) 115.9 (11.9) 0.35 (mmHg) Maternal diastolic BP67.8 (9.5) 68.4 (9.3) 0.76 (mmHg) Maternal heart rate (bpm) 76.0 (10.1)79.2 (13.2) 0.18 Fetal heart rate (bpm) 139.4 (10.1) 141.2 (11.1) 0.38Preblock VAS (cm) 8.0 (1.7) 7.8 (1.5) 0.62 Preblock use of Entonox 28(55.0%) 24 (47.1%) 0.55 Preblock pethidine (>2 hr 4 (7.8%) 6 (11.8%)0.74 ago) Preblock use of oxytocin 18 (35.3%) 14 (27.5%) 0.52 Preblockuse of Prostin 23 (45.1%) 20 (39.2%) 0.69 Preblock Artificial Rupture of33 (64.7%) 28 (54.9%) 0.42 Membranes Values are n (%) or mean (SD)

The incidence of breakthrough pain requiring epidural top-up by anattending anesthesiologist was significantly lower in the vAMB group (3patients [5.9%]) compared to the PCEA5 group (12 patients [23.5%]);(p=0.023). There were two patients in the PCEA5 group who experiencedtwo episodes of breakthrough pain. Patient profiles at the time ofbreakthrough pain are shown in Table 2 and mean survival times prior tofirst breakthrough pain illustrated in FIG. 3.

TABLE 2 Patient profile at breakthrough pain VAMB PCEA5 P- (N = 3) (N =12) VALUE† Time to 1^(st) breakthrough 299.7 (129.1) 296.1 (43.5)  0.99pain (min) Volume of epidural solution 35.0 (26.5) 51.4 (22.2) 0.25infused at 1^(st) breakthrough pain (ml) Cervical dilation at 1^(st) 5.3(2.1) 6.6 (2.3) 0.42 breakthrough pain (cm) VAS at 1^(st) breakthrough6.0 (0)   7.4 (1.5) 0.12 pain (cm) Oytocin infusion at 1^(st) 24.0(15.9) 16.5 (21.4) 0.30 breakthrough pain (ml/h) Sensory level at 1^(st)T8 [T6 to T8 [T6 to 0.89 breakthrough pain T10] T10] Bromage score at1^(st) 0 0 1.0 breakthrough pain Values are mean (SD) or median [range]†Nonparametric tests were applied due to small number of patients withbreakthrough pain

This improved analgesic efficacy was achieved without any significantdifference in the amount of local anesthetics consumed. Thetime-weighted mean hourly consumption of ropivacaine, inclusive ofclinician-administered supplemental boluses, were similar in both groups(10.0 mg [SD 3.0] in the vAMB group versus 11.1 mg (SD 3.2) in the PCEA5group; p=0.06). There was also no difference in the total amount ofropivacaine used (62.0 mg [SD 32.6] in the vAMB group versus 74.2 mg (SD34.0) in the PCEA5 group; p=0.07). Time to first patient demand-bolusfollowing CSE was similar (115.8 min [SD 65.2] in the vAMB group versus112.1 (SD 70.4) in the PCEA5 group; p=0.78).

The mean VAS score following CSE for the vAMB and PCEA5 study groupswere monitored for up to 10 h post CSE (FIG. 4). Mixed Model repeatedmeasurement analysis did not detect any difference in post-block serialpain scores nor sensory levels between the two groups, although thiscould be due to the study not being adequately powered for thesecomparisons. Maternal side effects experienced were also similar in bothgroups (Table 3). One parturient from Group PCEA5 had hypotension whichresolved following administration of IV ephedrine 5 mg bolus. Twopatients in Group PCEA5 had fetal bradycardia requiring administrationof IV Terbutaline 0.25 mg. Two patients in Group vAMB had fetalbradycardia, with one being resolved spontaneously and the otherrequiring IV Terbutaline 0.5 mg. None of the four parturients requiredan emergency cesarean section.

TABLE 3 Side effects of block VAMB PCEA5 (N = 51) (N = 51) P-VALUEShivering 23 (45.1%) 26 (51.0%) 0.69 Pruritus 29 (56.9%) 27 (52.9%) 0.84Nausea 1 (2.0%) 1 (2.0%) 1.0 Vomiting 1 (2.0%) 2 (3.9%) 1.0 Maternalpyrexia 3 (5.9%) 4 (7.8%) 1.0 Maternal hypotension 0 1 (2.0%) 1.0 Fetalbradycardia 2 (3.9%) 2 (3.9%) 1.0 Values are n (%)

Parturients in both groups had similar mean durations of labour. Therewas no difference in the duration of the second stage of labour amongstparturients who delivered vaginally, either with or without instrumentalassistance. This was in spite of the significantly higher rate ofmachine-delivered background epidural boluses in Group vAMB [mean 10.9ml/h (SD 4.5)] compared to the mean background infusion rate of 4.8 ml/h(SD 1.0) in Group PCEA5 at full cervical dilatation (p<0.001). Twoparturients in Group PCEA5 had their epidural infusion stopped by theobstetrician during the second stage of labour. Neonatal outcomes suchas fetal birthweight and Apgar scores were similar (Table 4).

TABLE 4 Obstetric and Neonatal outcomes VAMB PCEA5 P- (N = 51) (N = 51)VALUE Duration of labour (min) 389.4 (202.9) 414.2 (181.3) 0.52 Durationof 2^(nd) stage 69.8 (48.9) 84.9 (57.9) 0.22 (min) Background epidural10.9 (4.5) 4.8 (1.0) <0.001 maintenance at full cervical dilatation(ml/h) Mode of delivery Normal Vaginal Delivery 33 (64.7%) 32 (62.7%)0.65 Instrumental delivery 5 (9.8%) 8 (15.7%) Cesarean delivery 13(25.5%) 11 (21.6%) Fetal birthweight (g) 3244.4 (392.5) 3083.5 (502.9)0.08 Neonatal Apgar Scores at 9 9 1.00 5 min Satisfaction Score 96.5(5.0) 89.2 (9.4) <0.001 Values are n (%) or mean (SD)

When asked to rate their overall labour analgesia experience,parturients in Group vAMB reported higher satisfaction scores comparedto those in PCEA5 (mean=96.5, SD=5.0 versus mean=89.2, SD=9.4respectively; p<0.001).

The results demonstrated that using variable-frequency automatedintermittent boluses in place of a continuous basal infusion in PCEA forlabour analgesia resulted in a reduced incidence of breakthrough painrequiring anesthesiologist supplementation and greater overall maternalsatisfaction without any increase in local anesthetic consumption.

The role of a basal infusion in PCEA has long been a topic of debate. Onone hand, studies have shown that PCEA with a basal infusion can reducethe incidence of breakthrough pain and reduce pain scores with noincrease in local anaesthetic consumption compared to a demand-onlyPCEA⁴⁻⁶. On the other hand, some investigators found that using a basalinfusion in a PCEA regimen may increase local anesthetic consumptionwithout improving analgesic efficacy^(7,8). The present inventionsuccessfully combines the advantages of administering patient-regulatedbackground epidural infusates in the form of intermittent bolusesinstead of a fixed continuous basal infusion in a PCEA regimen. Varyingthe frequency of automated mandatory boluses in tandem with thefrequency of patient demand-boluses improves the analgesic efficacy of aPCEA regimen, as shown in the reduced incidence of breakthrough painrequiring supplementation by an anesthesiologist. The lack of differencein local anesthetic consumption between the two groups is likely due tothe auto-regulatory feature of the vAMB regimen, which minimizes drugusage in early labour when pain is less intense and allows greater drugconsumption to match the escalating pain of advanced labour. Indeed, asignificantly higher rate of machine-delivered background epiduralboluses in Group vAMB compared to the mean basal infusion rate in GroupPCEA5 at full cervical dilatation was found. We postulate that this mayhave alleviated perineal pain more effectively and thus contributed tothe observed increase in maternal satisfaction in Group vAMB. No adverseeffects resulting from the higher consumption of local anesthetic duringadvanced labour were detected, as shown by the duration of second stage,modes of delivery and neonatal outcomes being similar in both groups.Although patient profiles at the first episode of breakthrough pain werelargely similar, the number of patients whose data we analyzed was toosmall to draw any meaningful conclusion.

The results show that variable-frequency automated mandatory boluses aresuperior to a constant background infusion in PCEA for the maintenanceof labour epidural analgesia. A reduction in the need foranesthesiologist-administered supplementation of the epidural block notonly increases maternal satisfaction but may also be important inreducing workload at a busy tertiary obstetric unit.

REFERENCES

-   1. Van der Vyver M, Halpern S, Joseph G. Patient-controlled epidural    analgesia versus continuous infusion for labour analgesia: a    meta-analysis. Br J Anaesth 2002; 89:459-65.-   2. Boutros A, Blary S, Bronchard R, Bonnet F. Comparison of    intermittent epidural bolus, continuous epidural infusion and    patient controlled-epidural analgesia during labor. Int J Obstet    Anesth, 1999; 4: 236-41-   3. D'Angelo R. New techniques for labor analgesia: PCEA and CSE.    Clin Obstet Gynecol 2003; 46:623-32.-   4. Ferrante F M, Rosinia F A, Gordon C, Datta S. The role of    continuous background infusions in patient-controlled epidural    analgesia for labor and delivery. Anesth Analg 1994; 79:80-84.-   5. Missant C, Teunkenst A, Vandermeersch E, Van de Velde M. Patient    controlled epidural analgesia following combined spinal-epidural    analgesia in labour: the effects of adding a continuous epidural    infusion. Anaesth Intensive Care 2005; 33:452-456.-   6. Bremerich D H, Waibel H J, Mierdl S, et al. Comparison of    continuous background infusion plus demand dose and demand-only    parturient-controlled epidural analgesia (PCEA) using ropivacaine    combined with sufentanil for labor and delivery. Int J Obstet Anesth    2005; 14:114-120.-   7. Petry J, Vercauteren M, Van Mol I, et al. Epidural PCA with    bupivacaine 0.125%, sufentanil 0.75 microgram and epinephrine 1/800    000 for labor analgesia: is a background infusion beneficial? Acta    Anaesthesiol BeIg 2000; 51:163-166.-   8. Boselli E, Debon R, Cimino Y, et al. Background infusion is not    beneficial during labor patient-controlled analgesia with 0.1%    ropivacaine plus 0.5 mg/ml sufentanil. Anesthesiology 2004;    100:968-972.

1. A computer-implemented method for controlling dispensing of at leastone biologically active agent in intermittent doses over discretepredefined time periods, comprising the steps of: (i) initiating thedispensing of the biologically active agent in intermittent doses at afirst background dosage rate; and (ii) adjusting to a background dosagerate according to the number of input signals received over eachpredefined time period from a signalling device.
 2. The method accordingto claim 1, wherein step (ii) comprises either: (a) increasing thebackground dosage rate if the frequency of the input signals increases;or (b) decreasing the background dosage rate if the frequency of theinput signals decreases.
 3. The method according to claims 1 or 2,further comprising additionally dispensing a signal-induced dose of thebiologically active agent, in response to an input signal from asignalling device.
 4. The method according to any one of the precedingclaims, further comprising applying a lockout time period afterdispensing each intermittent dose and/or signal-induced dose wherein nofurther signal-induced and/or intermittent doses of the biologicallyactive agent are dispensed.
 5. The method according to any one of claims1 to 3, further comprising applying a lockout time period afterdispensing each intermittent dose and/or signal-induced dose wherein nofurther signal-induced doses of the biologically active agent aredispensed.
 6. The method according to any one of the preceding claims,wherein if the number of input signals received from the signallingdevice exceeds a predefined number, an alert signal is generated.
 7. Themethod according to any one of the preceding claims, further comprisingcapping the background dosage rate of the intermittent doses and/or thesignal-induced doses at a predefined maximum rate.
 8. The methodaccording to any one of the preceding claims, wherein the biologicallyactive agent is for use in administering to a subject.
 9. The methodaccording to any one of the preceding claims, wherein the biologicallyactive agent is for use in epidural administration to a subject.
 10. Acomputer-implemented method for controlled administration of at leastone biologically active agent to a subject, comprising the steps of: (i)initiating the dispensing of the biologically active agent inintermittent doses for administration to the subject at a firstbackground dosage rate; and (ii) adjusting to a background dosage rateaccording to the number of input signals received over each predefinedtime period from a signalling device.
 11. The method according to claim10, wherein step (ii) comprises either: (a) increasing the backgrounddosage rate if the frequency of the input signals increases; or (b)decreasing the background dosage rate if the frequency of the inputsignals decreases.
 12. The method according to claims 10 or 11, furthercomprising additionally dispensing a signal-induced dose of thebiologically active agent, in response to an input signal from thesignalling device.
 13. The method according to any one of claims 10 to12, further comprising applying a lockout time period after dispensingeach intermittent dose and/or signal-induced dose wherein no furthersignal-induced and/or intermittent doses of the biologically activeagent are dispensed.
 14. The method according to any one of claims 10 to13, further comprising applying a lockout time period after dispensingeach intermittent dose and/or signal-induced dose wherein no furthersignal-induced doses of the biologically active agent are dispensed. 15.The method according to any one of claims 10 to 14, wherein if thenumber of input signals received from the signalling device exceeds apredefined number, an alert signal is generated.
 16. The methodaccording to any one of claims 10 to 15, further comprising capping thebackground dosage rate of the intermittent doses and/or thesignal-induced doses at a predefined maximum rate.
 17. The methodaccording to any one of claims 10 to 16, wherein the input signals arecontrolled by a user operating the signalling device.
 18. The methodaccording to any one of claims 10 to 17, wherein the administrationcomprises epidural administration.
 19. The method according to any oneof the preceding claims, wherein the method includes utilizing at leastone dispensing device for dispensing the biologically active agent. 20.The method according to any one of the preceding claims, wherein thedispensing device comprises a pump and/or syringe.
 21. The methodaccording to any one of the preceding claims, wherein the biologicallyactive agent comprises an analgesic or an anaesthetic.
 22. A softwareexecutable by a computer system to cause the computer system to performthe method according to any one of claims 1 to
 21. 23. A computerprogram product comprising a software executable by a computer system tocause the computer system to perform the method according to any one ofclaims 1 to
 21. 24. The computer program product according to claim 23,wherein the computer program product comprises a tangible computerprogram product.
 25. The tangible computer program product according toclaim 24, comprising a tangible recording, storage and/orcomputer-readable media.
 26. A computer system, programmed to performthe method according to any one of claims 1 to
 21. 27. The computersystem according to claim 26, wherein the computer system is operativelyconnected to at least one dispensing device.
 28. A dispensing systemcomprising a computer system operatively connected to at least onedispensing device, wherein the dispensing system is configured toperform the method according to any one of claims 1 to
 21. 29. Thecomputer system according to claim 27 or the dispensing system accordingto claim 28, wherein the dispensing device comprises a pump and/orsyringe.